Diabetes mellitus is a serious illness that affects an increasing number of people across the world. Projections from the International Diabetes Federation suggest that by 2025 there will be a total of 380 million people worldwide suffering from diabetes. The incidence of diabetes in many countries is escalating in parallel with an upward trend in obesity. Serious consequences of diabetes include increased risk of stroke, heart disease, kidney damage, blindness, and amputation. Cardiovascular diseases are the cause of death of more than 70% of patients with Type 2 diabetes mellitus (T2DM) [B. Pourcet et al. Expert Opin. Emerging Drugs 2006, 11, 379-401.]
Diabetes is characterized by decreased insulin secretion and/or an impaired ability of peripheral tissues to respond to insulin, resulting in increased plasma glucose levels. There are two forms of diabetes: insulin-dependent and non-insulin-dependent, with the great majority of diabetics suffering from the non-insulin-dependent form of the disease, known as type 2 diabetes or non-insulin-dependent diabetes mellitus (NIDDM). Because of the serious consequences, there is an urgent need to control diabetes.
Treatment of NIDDM generally starts with weight loss, a healthy diet and an exercise program. These factors are especially important in addressing the increased cardiovascular risks associated with diabetes, but they are generally ineffective in controlling the disease itself. There are a number of drug treatments available, including insulin, metformin, sulfonylureas, acarbose, thiazolidinediones, GLP-1 analogues, and DPP IV inhibitors. However, several of these treatments have disadvantages which may include one or more of the following: hypoglycemia, weight gain, intestinal discomfort, and a loss of efficacy over time.
Although drugs have been approved for the treatment of diabetes using a number of different mechanisms, and many other drugs are being evaluated clinically, there remains a need to invent new compounds for the treatment of diabetes. It has recently been disclosed that the results of the United Kingdom Prospective Study indicate that over time, a decline is seen in the beta cell function of diabetic patients irrespective of whether they were being treated with diet, sulfonylureas, metformin, or insulin [R. R. Holman Metabolism 2006, 55, S2-S5].
GPR119 is a 335 amino acid protein [R. Fredriksson et al. FEBS Lett. 2003, 554, 381-388] which is expressed on the beta-cells of pancreatic islets [Z.-L. Chu et al. Endocrinol. 2007, 148, 2601-2609] and also in the GI tract [Z.-L. Chu et al. Endocrinol. 2008, 149, 2038-2047]. The protein belongs to the G-protein coupled receptor family, and several candidates have been proposed as the endogenous ligand, including oleoylethanolamide (OEA), N-oleoyldopamine, and olvanil [H. A. Overton et al. Brit. J. Pharmacol. 2007, 1-6].
GPR119 plays a role in glucose-dependent secretion of insulin, and the possibility of targeting the GPR119 receptor for the treatment of diabetes is supported by a number of studies in cell lines and in animals. Activation of the GPR119 receptor by lysophosphatidylcholine enhances glucose-dependent insulin secretion in a mouse pancreatic β-cell line, and the insulin secretion can be blocked using GPR119-specific siRNA [T. Soga et al. Biochem. Biophys. Res. Commun. 2005, 326, 744-751].
There is a need, therefore, for activators of the GPR119 receptor for the treatment of diseases such as diabetes.